Assessment of newborn neuropsychomotor development born with exposure to SARS-CoV-2 in the perinatal period using the Bayley III scale at 6 months of age

Highlights • The perinatal repercussions of the SARS-CoV-2 virus have not yet been elucidated.• Few reports in the literature indicate damage to the Neuro Psychomotor Development (NPMD) of children born during the COVID-19 pandemic, but its mechanisms are not clearly established.


Introduction
2][3] It is estimated that more than 200 million births have occurred since the beginning of the SARS-CoV-2 pandemic and, even the most conservative estimates, calculate that millions of babies around the world were exposed to the virus during pregnancy during this period. 4ransmission of SARS-CoV-2 occurs mainly through droplets from infected people or through contact with contaminated biological material.The spectrum of disease resulting from SARS-CoV-2 infection is called COVID-19 and can range from asymptomatic infection to pneumonia, which can lead to acute ventilatory failure, septic shock, organ failure, and death.][6][7][8] Regarding the vertical transmission of SARS-CoV-2 from mother to fetus, although rare and not completely understood, previous outbreaks of other coronavirus variants and exposures to other viruses (including the Human Immunodeficiency Virus -HIV) suggest that serious infections during pregnancy may be associated with both risks to maternal health and a greater number of adverse outcomes in the newborn. 4hese factors contributed to the hypothesis that newborns of mothers infected with SARS-CoV-2 during pregnancy may have a greater risk of stillbirth, prematurity, brain damage in the fetus and consequent changes in Neuropsychomotor Development (NPMD) due to the known ability of this virus to damage nerve cells. 4,7[10] Deoni SCN et al. ( 2021) found that COVID-19 changed the landscape of child health, as children born between 2020 and 2021 were placed in an economic, psychosocial and educational environment different from that which existed prior to the COVID-19 pandemic. 9Shuffrey LC et al. (2022) also evaluated the NPMD of babies exposed to SARS-COV-2 in the intrauterine environment, but their results showed that exposure to maternal virus infection was not associated with development damage. 4However, compared to the historical cohort, newborns during the pandemic had lower scores in the gross motor, fine motor, and personal-social domains.
In the literature, there are several instruments designed to assess child development, all of which have their advantages and limitations. 11he Bayley III Child Development Scales assess children between one and 42 months of age and have a screening test, The Bayley Infant Neurodevelopment Screener (BINS), which identifies possible delays in the NPMD and indicates whether a more extensive evaluation is necessary.[11][12][13][14][15] Orioli PA et al. (2022) showed in a systematic review that despite presenting a sensitivity of 33.3 %, specificity of 98 % and level of evidence C, the Bayley III Scales can be used to monitor gains after interventions.14 This level of evidence is due to few studies and small samples when applying this Scale, but it is a tool validated in the Brazilian population, with standardized language, which can be applied by trained health professionals and duly certified for this purpose, being considered gold standard.1,11,14 Knowledge of the NPMD of newborns exposed to SARS-CoV-2 through a specific scale validated for the Brazilian population is important for the detection and prevention of possible functional changes.4,[8][9][10] Monitoring children born during the COVID-19 pandemic is necessary for the early identification of children at risk for delays in NPMD.
Thus, the objective of this study was to describe the maternal and newborn characteristics and evaluate the NPMD of those exposed to SARS-CoV-2 in the perinatal period using the Bayley III Scale Screening Test at six months of chronological age, aiming to identify possible changes in the motor, cognitive and language domains.

Methods
This is a prospective unicentric study, including newborns at the Hospital das Clínicas of the Faculty of Medicine of USP (HCFMUSP) and admitted to the Neonatal Intensive Care Center (CTIN1) of the Children's Institute of FMUSP from to 04/26/2020 on 2/17/21.
Newborns whose mothers had flu-like syndrome and RT-PCR (at the time of birth) for SARS-CoV-2 positive and/or positive serology during the gestational period were included.
Newborns whose birth took place in external institutions, newborns with major congenital malformations (examples: complex heart diseases, genetic syndromes, known alterations of the nervous system), or when the legal guardian's acceptance to participate in the research were not obtained.
For the children included in the study, childcare consultations were scheduled at the Neonatology Outpatient Clinic of the HCFMUSP Children's Institute, so that an assessment was mandatory at 6 months of chronological age.
During the consultations, the Bayley III Scale Screening Test 12−15 was applied.From there, the children were classified as "low risk", "moderate risk" or "high risk" in each of the domain assessments: cognitive, receptive language, expressive language, fine motor, and gross motor.Those classified as "moderate risk", or "high risk" received guidance on NPMD incentives and were advised to maintain follow-up to carry out the assessment in the following months.
The assessments were carried out by two pediatricians and neonatologists previously trained and qualified to apply and interpret the results of the Bayley III Scale and reviewed by a physiotherapist qualified to use these assessment scales.

Statistical analysis
The data were tabulated in the Excel 2019 program (Microsoft Corporation, USA).Descriptive statistics used measures of central dispersion (means and Standard Deviations [SD], medians and Interquartile Ranges − IIQ: 25 %-75 % percentiles), as well as absolute and relative frequencies, as indicated.
The analyses were performed using R: A language and environment for statistical computing.Version 4.3.0.R Foundation for Statistical Computing, Vienna, Austria.URLhttps://www.R-project.org/.
The variables tested in the bivariate models were prematurity, length of stay, birth weight, antibiotics, parenteral nutrition, resuscitation, Apgar in the 1 st and 5 th minute, acute fetal distress and type of delivery.
Bivariate regression models were constructed for the outcomes: cognitive competence, in receptive language, expressive language, fine and gross motor skills, at six months of chronological age.

Results
During the period of this unprecedented study, 50 babies were born at the Institution, 41 of which met the study inclusion criteria.However, 35 patients were included in the study (Fig. 1) due to the difficulties imposed by the beginning of the pandemic, such as mobility restrictions, socioeconomic issues and distance logistics for patients who were referred to a tertiary center far from their residence at the time of birth.
Data from 41 patients were analyzed.Maternal epidemiological data and birth conditions are found in Table 1.
Data on the birth conditions and evolution during hospitalization of the newborns can be seen in Table 2.As in Table 3, complementary exams carried out on the newborns throughout the period of hospital stay and outpatient follow-up are shown.
Table 4 shows the assessment of the NPMD of newborns at six months of chronological age, carried out using the Bayley III Scale Screening Test.The newborns were evaluated in the cognitive, receptive language, expressive language, fine motor and gross motor domains and classified according to the score achieved as: "low risk", "moderate risk" and "high risk".
Figure 2 shows the scatter plot in which it is possible to observe the classifications achieved by the evaluated patients (low risk / moderate risk / high risk) in the five domains evaluated (cognitive / receptive language / expressive language / fine motor / gross motor) at six months of age.
For all other variables in binary combinations with the outcomes, there were no significant risks.

Discussion
Of the 41 mothers whose children were included in the study, four required orotracheal intubation at the time of birth (9.8 %), two of   whom died.The maternal mortality rate in this study was 9.8 %, as four mothers died during hospitalization.Of these six mothers (14.5 % of the total) with the worst clinical evolution (orotracheal intubation and/or death), all had a cesarean section, in four of them there was an indication to interrupt the pregnancy due to severe COVID-19, one of them presented acute fetal distress and decompensation of hypertensive disorders of pregnancy.
Pregnant women are at greater risk of acquiring viral respiratory infections and developing serious clinical conditions due to the physiological, immunological and cardiopulmonary changes inherent to pregnancy. 1,6,16,17The information in the literature on this issue is still conflicting.While some point out that the clinical evolution of pregnant women with COVID-19 was similar to that of adults with COVID-19, 1,16 other authors suggest that pregnant women may have worse outcomes, including eclampsia, admission to the Intensive Care Unit (ICU), use of mechanical ventilation and increased morbidity and mortality. 6,17,18e premature birth rate in present study sample was 46.3 % and probably reflects the effects of COVID-19 on maternal health.Among 19 premature births, 17 were cesarean sections (89.45 %) and the study cesarean rate was 80.5 %.The literature states that COVID-19 during pregnancy was not associated with spontaneous premature birth. 16However, depending on the evolution of maternal respiratory failure, hypoxemia can alter the placental flow, 17 contributing to the pregnancy being interrupted before full-term birth (before 37 weeks of gestation).Another study [16] points out that the prematurity rate was also influenced by issues unrelated to COVID-19, such as severe pre-eclampsia and premature rupture of ovular membranes. 16he lowest birth weight among the patients included in the sample was 680g, with an average weight of 2,651g.The median weight curve in the Fenton table was 51 %.Only two newborns were classified as small for gestational age (4.9 %), that is, weighing less than the 10 th percentile curve of the Fenton weight table.Apparently, in this sample,  COVID-19 was not a risk factor for intrauterine growth restriction, a result also found in other studies. 1,16,18garding birth conditions, more than 80 % of the sample (82.9 %) did not require resuscitation maneuvers.Four patients (9.7 %) had an APGAR between 0 and 3 in the first minute and of these, 2 (4.8 %) remained with an APGAR than or equal to 3 in the fifth minute of life, therefore being classified as severely asphyxiated.
Of the total number of newborns, only 5 (12.1 %) had a fifth-minute APGAR score lower than 7.The sample, therefore, was predominantly composed of newborns who did not require resuscitation and did not suffer from perinatal asphyxia/depression, which could increase the risk of delays in the NPMD.
The absence of high rates of perinatal asphyxia related to COVID-19 is similar to other studies including pregnant women with COVID-19, which did not present newborns with a higher risk of perinatal asphyxia. 1,16,18 the 41 newborns included in the study, 2 (4.8 %) were positive in the PCR for COVID-19, collected in the maternity ward.
Subsequently, during outpatient follow-up, IgG for COVID-19 was collected from 36 patients, with an average age of three to four months of age.Of these, 6 (16.6 %) showed reactive IgG.Among those with positive PCR initially, both also had positive serologies.The data available in the literature to date highlight that transplacental transmission remains controversial. 1,16,17,19Studies 1 highlights that although possible, it is apparently rare and unlikely. 6,20egarding the diagnostic methods used, in the present study, two newborns presented positive PCR (collected upon admission) and serology (IgG, collected on an outpatient basis).However, it is not possible to prove transplacental transmission, as in most available studies, due to the high possibility of neonatal transmission due to possible failures in adequate isolation. 6,16,19,21 the time of discharge, only eight newborns (19.5 %) were exclusively breastfed, 30 (73.2 %) were artificially breastfed and 3 (7.3%) were mixed breastfed.This low rate of breastfeeding reflected the need to accommodate newborns separately from their mothers, during hospitalization during the COVID-19 pandemic, following institutional protocol.

Bayley III screening test
Thirty-five infants were evaluated for MPND using the Bayley III Scale Screening Test when they were approximately six months of chronological age.
Aiming to minimize the effects of prematurity on the NPMD assessment, all premature infants included were evaluated considering their corrected gestational age.In this way, the 12 premature babies evaluated had their results based on their corrected ages, allowing them to be evaluated according to the expected acquisitions for their corrected age and minimizing the bias that prematurity could possibly represent in the detection of PMND delay.
In a recent study, it was suggested that despite showing a tendency to lower scores at 6-months of age, premature babies show greater gains in cognitive scores throughout the first year of life, suggesting a capacity for recovery despite restrictions imposed by premature birth. 22n the cognitive analysis of the 35 infants, 26 of them were classified as low risk (74.3 %), eight were classified as moderate risk (22.9 %) and 1 (2.9 %) as high risk for cognitive delay.
Language assessment was subdivided into receptive and expressive language.Only 13 infants (37.1 %) were classified as low risk in receptive language, 18 (51.4%) were classified as moderate risk and 4 (11.4 %) as high risk.Thus, receptive language was the most affected area in the present study, as the majority of newborns presented cognitive incompetence (it was classified as "moderate risk" or "high risk").
The motor assessment was subdivided into fine and gross motor skills.In the fine motor assessment, 20 children (57.1 %) were classified as low risk, 11 (31.4 %) as moderate risk and 4 (11.4 %) as high risk.In the assessment of gross motor skills, only 18 infants (51.4 %) were classified as low risk, 13 (37.1 %) as moderate risk and 4 (11.4 %) as high risk, which configured gross motor skills as the second most affected area, as practically half of the RNs did not reach a score that would classify them as low risk in the domain.
The application of the Bayley III Scales Screening Test in this study suggests that there was damage to the NPMD in infants exposed to COVID-19 in the perinatal period.However, it is necessary to continue monitoring these newborns to assess whether these changes are transient, permanent, or evolutionary.Therefore, all infants included in the evaluation at six months of chronological age were to be monitored for up to one year of life at the institution's Neonatology Outpatient Clinic.
Among the limitations of the findings of the present study, the authors include the difficulty in finding the specific cause of the changes in the NPMD of the sample, as they may be due to the repercussions of maternal COVID-19 disease during the gestational period, the direct influence of the virus and/or be due to changes in the socioeconomic conditions of the population during the pandemic (example: reduction of motor stimuli, social isolation).The logistic regression analysis in this sample has limitations, as it is a small sample.Due to the dependency relationship between the significant variables (prematurity, low birth weight, length of hospital stay), multivariate analysis was not possible.

Conclusion
The assessment of NPMD of newborns exposed to SARS-CoV-2 in the perinatal period using a specific scale validated for the Brazilian population is not described in the literature.
The sample in this study presented lower scores in the Receptive Language and Gross Motor domains in the Bayley III Scales screening test, which may suggest possible impairment of NPMD in children exposed to SARS-CoV-2 in the perinatal period.
Infants included in the study must be monitored and their development monitored in order to try to clarify whether changes in NPMD are permanent, transitory or evolutionary.

Fig. 1 .
Fig. 1.Description of newborns in the period, those with inclusion criteria and those who appeared for evaluation by the Bayley III Screening Test.

Fig. 2 .
Fig. 2. Scatter plot of the Screening Test classifications in the domains assessed at six months of age.

Table 1
Maternal data and birth conditions.

Table 2
Data and clinical evolution of newborns.

Table 4
Bayley III Scale Screening Test applied at 6-months of chronological age of newborns.